The mission of the HIV Prevention Trials Network (HPTN) is to discover and develop interventions that can be used globally to prevent sexual and/or parenteral transmission of HIV. Our research encompasses the testing of novel biomedical and behavioral approaches. We seek HIV prevention strategies that are effective, safe, feasible, and sustainable, even in resource-limited settings. The incumbent HPTN has built field site research capacity in 16 developing countries. In the international HIVNET and the HPTN, we have recruited 31,250 HIV uninfected (principally) and infected persons into 38 trials (19,500 by the incumbent HPTN since 1999). Subjects are almost exclusively high risk, including adolescents and acutely infected persons. Focusing on resource-constrained countries in Africa, Asia, So. America, and E. Europe, as well as high incidence populations in the U.S., our highest impact trials have literally changed global public health practice. We are dividing the current HPTN agenda into three parts, with our perinatal group partnering to create IMPAACT, and our microbicide group spearheading the MTN. The new HPTN focus is fourfold: (1) antiretroviral therapy and co-infection therapy for viral load reduction and prevention of HIV transmission, (2) treatment of sexually transmitted infections (STI) to lower HIV transmission risk, (3) treatment of substance abuse and addiction, including injection drug use and stimulants (cocaine and methamphetamines) to reduce HIV transmission, and (4) behavioral risk reduction with biological endpoints. We use randomized controlled trials with HIV incidence endpoints in uninfected persons. For prevention research among acutely and chronically HIV-infected persons, we study incidence of non-HIV STIs, lowering of HIV viral load, and/or HIV incidence in sexual or needle-sharing partners. We propose to complete five ongoing HPTN trials and to transition an additional six ongoing HPTN trials to the IMPAACT and MTN networks, if funded. We present eight new trial concepts, five for prevention of HIV infection, one for detection and intervention among acutely infected persons (pre-seroconversion), and two focused on prevention among HIV-seropositive persons. Our risk populations include high risk heterosexuals, men who have sex with men, substance abusers, and, for selected trials, their sexual or needle-sharing partners. Our proposed affiliated Clinical Trials Units serve at-risk populations on five continents. The HPTN Leadership Group is diverse and includes experienced ethics experts and community leaders. HPTN governance is designed to develop and complete trials efficiently. We emphasize concepts of high potential public health impact, focusing on existing technologies that can be brought immediately into practice. Therefore, our agenda is complementary to long-term investments (finding a cure, vaccine, or microbicide).